Autophagy of partially modified proteins is visualized as the rate limiting step in the enhanced intracellular proteolysis induced by nutritional deprivation. It is postulated that the formation of glutathione-mixed disulfides can serve as a metabolic signal whereby the cell can recognize proteins for autophagic sequestration. Such mixed disulfides are likely to decrease the compactness of folding of the protein, expose more hydrophobic regions within the molecule, enhance the aggregation and absorption of the protein to some intracellular membranes and eventually leads to the intralysosomal entrapment of the altered protein. It is suggested that insulin and amino acids, which have been shown to decrease hepatic protein degradation rapidly, may do so by decreasing the formation of glutathione-protein mixed disulfides either directly by reversing the thiol transferase reaction or indirectly by altering the metabolism of reduced and oxidized glutathione.